Urinary bladder tumors arise from the transitional epithelium and rarely penetrate the bladder?s detrusor muscle. Thus, complete tumor resection is frequently possible using a transurethral instrument to remove the tumor at its root without total bladder removal. Unfortunately, genomic instability is rampant throughout the transitional epithelium in most patients and tumor relapse is common despite complete tumor removal. As a result, patients require lifelong endoscopic monitoring, multiple biopsies, and repeated intravesical therapies. mTOR inhibition treats and prevents bladder cancer (BC) in preclinical models and is thought to work by directly targeting bladder tumors. While this dogma is true, it provides an incomplete picture of the potential activity of this therapy in BC. Our preliminary data shows favorable pharmacokinetic and pharmacodynamic activity of low dose rapamycin in bladder tissues. We also show that a novel encapsulated formulation of rapamycin (eRapa) modulates immune responses and these effects favor improved anti-BC immunity and improved responses towards BCG, which is standard-of-care immune therapy for high-grade non-muscle invasive bladder cancer (BC). We propose investigating eRapa for secondary cancer prevention in patients with newly diagnosed non-muscle invasive bladder cancer. Aim 1 conducts a phase II double-blind randomized controlled trial of long-term (one year) prevention with eRapa versus placebo. Outcome measures include efficacy, tolerability, and effects on cognition and physical function. Efficacy is assessed through standard-of-care surveillance monitoring to capture relapses and to estimate recurrence-free survival. Tolerability is measured with validated BC-specific symptom assessments and global quality of life questionnaires. Cognition and physical function are assessed with validated executive/memory function testing and by physical performance testing. Aim 2 test the hypothesis that eRapa improves immune function in patients with BC by examining the effects of eRapa on circulating immune cells, including memory T cell differentiation, and tumor-specific immunity. For patients concurrently receiving intravesical BCG, the ability of eRapa to boost BCG-specific immunity is tested. If successful, this project will facilitate a phase III registration trial for a new secondary prevention agent for BC patients. In addition, this work provides foundational insights into immune events in elderly BC patients that are useful to developing other cancer immunotherapies.